Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene
Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene
复制标题
家族性阵发性运动源性运动障碍与 KCNA1 基因突变有关
DOI：
10.1093/hmg/ddx430
复制
发表时间：
2018-02-15
影响因子：
3.5
通讯作者：
Tang, Bei-Sha
中科院分区：
文献类型：
--
作者：
Yin, Xiao-Meng;Lin, Jing-Han;Tang, Bei-Sha
阵发性运动诱发性运动障碍（PKD）是一种异质性运动障碍，其特征是由突然运动引发的反复运动障碍发作。PRRT 2是PKD的第一致病基因。然而，它只负责大约一半的受影响的个人，表明其他基因座是最有可能参与这种疾病的病因。为了探索PRRT 2阴性PKD的潜在致病基因，我们使用了包括连锁分析、全外显子测序和拷贝数变异分析的组合策略来检测PKD家族中的遗传变异。我们在12号染色体（12p13.32-12p12.3）上鉴定了一个连锁位点，并在钾电压门控通道亚家族A成员1 KCNA 1中检测到一个新的杂合突变c.956 T>G（p.319 L>R）。对另外58例中国PKD患者进行全外显子组测序，发现在另一个家族中存在另一种新的KCNA 1基因突变[c.765 C>A（p.255 N>K）]。生化分析表明，L319 R突变体通过蛋白酶体途径加速蛋白质降解，并破坏Kv1.1通道的膜表达。转染HEK 293细胞的电生理学检查表明，L319 R和N255 K突变体均导致钾电流降低和各自的门控特性改变，对Kv1.1野生型通道具有显性负效应。我们的研究表明，KCNA 1的这些突变导致Kv1.1通道功能障碍，从而导致家族性PKD。目前的研究进一步扩展了这种疾病的基因型谱，表明Kv1.1通道功能障碍可能是PKD的潜在缺陷之一。
Paroxysmal kinesigenic dyskinesia (PKD) is a heterogeneous movement disorder characterized by recurrent dyskinesia attacks triggered by sudden movement. PRRT2 has been identified as the first causative gene of PKD. However, it is only responsible for approximately half of affected individuals, indicating that other loci are most likely involved in the etiology of this disorder. To explore the underlying causative gene of PRRT2-negative PKD, we used a combination strategy including linkage analysis, whole-exome sequencing and copy number variations analysis to detect the genetic variants within a family with PKD. We identified a linkage locus on chromosome 12 (12p13.32-12p12.3) and detected a novel heterozygous mutation c.956 T>G (p.319 L>R) in the potassium voltage-gated channel subfamily A member 1, KCNA1. Whole-exome sequencing in another 58 Chinese patients with PKD who lacked mutations in PRRT2 revealed another novel mutation in the KCNA1 gene [c.765 C>A (p.255 N>K)] within another family. Biochemical analysis revealed that the L319R mutant accelerated protein degradation via the proteasome pathway and disrupted membrane expression of the Kv1.1 channel. Electrophysiological examinations in transfected HEK293 cells showed that both the L319R and N255K mutants resulted in reduced potassium currents and respective altered gating properties, with a dominant negative effect on the Kv1.1 wild-type channel. Our study suggests that these mutations in KCNA1 cause the Kv1.1 channel dysfunction, which leads to familial PKD. The current study further extended the genotypic spectrum of this disorder, indicating that Kv1.1 channel dysfunction maybe one of the underlying defects in PKD.